tbuckley/cabot-search huggingface dataset:
INBRX-120, a CD8α-targeted detuned IL-2 that selectively expands and activates tumoricidal effector cells for safe and durable in vivo responses
Authors: Florian J Sulzmaier, Nadja Kern, Sae Jeong Ahn, Anya Polovina, Jason Ho, Abrahim Hussain, Garrett Cyprus, Chelsie Macedo, Rajay Pandit, William Crago, Emily Rowell, John C Timmer, Brendan P Eckelman
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background As a major driver of lymphocyte proliferation and activation interleukin 2 (IL-2) is a crucial mediator for antitumor responses. Despite promising activity in a subset of patients, wider therapeutic utility of IL-2 (aldesleukin) has been hampered by severe dose-limiting toxicities, the expansion of immunosuppressive regulatory T cells and a poor pharmacokinetic (PK) profile. Recent engineering efforts, including non-α IL-2 variants, have lowered the toxicity profile, but have yet to induce meaningful antitumor activity in a wider patient population. Methods We engineered INBRX-120, a CD8α-targeted Cisleukin™ molecule consisting of an affinity tuned IL-2 (IL2-x) connected to two high affinity CD8α-specific single domain antibodies via an effector-silenced Fc domain. To show that this large affinity differential enables directed IL-2 cis-signaling exclusively on CD8α-expressing tumoricidal effector cell populations, INBRX-120 effects on target cell expansion, activation and antitumor activity were tested in vitro. In vivo antitumor efficacy was evaluated in syngeneic mouse models alone or in combination with programmed cell death protein-1 (PD-1) blockade. Preclinical safety, as well as pharmacodynamic (PD) and PK profiling was carried out in non-human primates. Results INBRX-120 effectively expanded and enhanced the cytotoxic capacity of CD8 T cells and natural killer cells towards tumor cells without affecting regulatory T cells in vitro and in vivo. In syngeneic mouse models, INBRX-120 surrogate showed safe, potent, and durable antitumor efficacy alone and in combination with PD-1 blockade. In non-human primates, INBRX-120 expanded and activated CD8α-expressing effector cells, showed a favorable PK profile, and was well tolerated up to a dose of 1 mg/kg. Conclusions Through its unique cis-signaling activity on CD8α-expressing effector cells, INBRX-120 overcomes the major limitations of IL-2-based therapy and effectively harnesses IL-2’s potent intrinsic antitumor activity. This novel therapeutic strategy promises safer clinical activity that could induce meaningful antitumor efficacy in a wider set of patients with various cancer indications.
Novel banana lectin CAR-T cells to target pancreatic tumors and tumor-associated stroma
Authors: Mary K McKenna, Ada Ozcan, Daniel Brenner, Norihiro Watanabe, Maureen Legendre, Dafydd G Thomas, Christopher Ashwood, Richard D Cummings, Challice Bonifant, David M Markovitz, Malcolm K Brenner
Journal: Journal for ImmunoTherapy of Cancer (2023)

Cell therapies for solid tumors are thwarted by the hostile tumor microenvironment (TME) and by heterogeneous expression of tumor target antigens. We address both limitations with a novel class of chimeric antigen receptors based on plant lectins, which recognize the aberrant sugar residues that are a 'hallmark' of both malignant and associated stromal cells. We have expressed in T cells a modified lectin from banana, H84T BanLec, attached to a chimeric antigen receptor (H84T-CAR) that recognizes high-mannose (asparagine residue with five to nine mannoses). Here, we tested the efficacy of our novel H84T CAR in models of pancreatic ductal adenocarcinoma (PDAC), intractable tumors with aberrant glycosylation and characterized by desmoplastic stroma largely contributed by pancreatic stellate cells (PSCs).
Assessing the Discriminatory Ability of Diagnostic Criteria for Ulcerative Pyoderma Gangrenosum and Its Mimickers
Authors: Antonio Ji-Xu, William Liakos, Alexander Merleev, Marie-Charlotte Brüggen, Caroline A. Nelson
Journal: JAMA Dermatology (2023)

This comparative effectiveness research study assesses the discriminatory ability of diagnostic criteria for pyoderma gangrenosum.
Understanding the Social Determinants of Surgical Evaluation—Going Beyond Signs and Symptoms
Authors: Jonathan Carter
Journal: JAMA Surgery (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Lysine-specific histone demethylase 1A (KDM1A/LSD1) inhibition attenuates DNA double-strand break repair and augments the efficacy of temozolomide in glioblastoma
Authors: Salvador Alejo, Bridgitte E Palacios, Prabhakar Pitta Venkata, Yi He, Wenjing Li, Jessica D Johnson, Yihong Chen, Sridharan Jayamohan, Uday P Pratap, Kyra Clarke, Yi Zou, Yingli Lv, Korri Weldon, Suryavathi Viswanadhapalli, Zhao Lai, Zhenqing Ye, Yidong Chen, Andrea R Gilbert, Takayoshi Suzuki, Rajeshwar R Tekmal, Weixing Zhao, Siyuan Zheng, Ratna K Vadlamudi, Andrew J Brenner, Gangadhara R Sareddy
Journal: Neuro-Oncology (2023)

Abstract Background Efficient DNA repair in response to standard chemo and radiation therapies often contributes to glioblastoma (GBM) therapy resistance. Understanding the mechanisms of therapy resistance and identifying the drugs that enhance the therapeutic efficacy of standard therapies may extend the survival of GBM patients. In this study, we investigated the role of KDM1A/LSD1 in DNA double-strand break (DSB) repair and a combination of KDM1A inhibitor and temozolomide (TMZ) in vitro and in vivo using patient-derived glioma stem cells (GSCs). Methods Brain bioavailability of the KDM1A inhibitor (NCD38) was established using LS-MS/MS. The effect of a combination of KDM1A knockdown or inhibition with TMZ was studied using cell viability and self-renewal assays. Mechanistic studies were conducted using CUT&amp;Tag-seq, RNA-seq, RT-qPCR, western blot, homologous recombination (HR) and non-homologous end joining (NHEJ) reporter, immunofluorescence, and comet assays. Orthotopic murine models were used to study efficacy in vivo. Results TCGA analysis showed KDM1A is highly expressed in TMZ-treated GBM patients. Knockdown or knockout or inhibition of KDM1A enhanced TMZ efficacy in reducing the viability and self-renewal of GSCs. Pharmacokinetic studies established that NCD38 readily crosses the blood-brain barrier. CUT&amp;Tag-seq studies showed that KDM1A is enriched at the promoters of DNA repair genes and RNA-seq studies confirmed that KDM1A inhibition reduced their expression. Knockdown or inhibition of KDM1A attenuated HR and NHEJ-mediated DNA repair capacity and enhanced TMZ-mediated DNA damage. A combination of KDM1A knockdown or inhibition and TMZ treatment significantly enhanced the survival of tumor-bearing mice. Conclusions Our results provide evidence that KDM1A inhibition sensitizes GBM to TMZ via attenuation of DNA DSB repair pathways.
Epidemiologic and Genetic Associations of Endometriosis With Depression, Anxiety, and Eating Disorders
Authors: Dora Koller, Gita A. Pathak, Frank R. Wendt, Daniel S. Tylee, Daniel F. Levey, Cassie Overstreet, Joel Gelernter, Hugh S. Taylor, Renato Polimanti
Journal: JAMA Network Open (2023)

Importance Endometriosis is a common chronic gynecologic pathology with a large negative impact on women’s health. Beyond severe physical symptoms, endometriosis is also associated with several psychiatric comorbidities, including depression and anxiety. Objective To investigate whether pleiotropy contributes to the association of endometriosis with depression, anxiety, and eating disorders. Design, Setting, and Participants This genetic association study was performed between September 13, 2021, and June 24, 2022, in 202 276 unrelated female participants. Genotypic and phenotypic information from the UK Biobank was combined with genome-wide association statistics available from the Psychiatric Genomics Consortium (11 countries), the Million Veteran Program (US), the FinnGen study (Finland), and the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium (5 countries). Main Outcomes and Measures The main outcomes were the phenotypic and genetic associations of endometriosis with anxiety, depression, and eating disorders. Results A total of 8276 women with endometriosis (mean [SD] age, 53.1 [7.9] years) and 194 000 female controls (mean [SD] age, 56.7 [7.9] years) were included in the study. In a multivariate regression analysis accounting for age, body mass index, socioeconomic status, chronic pain–related phenotypes, irritable bowel syndrome, and psychiatric comorbidities, endometriosis was associated with increased odds of depression (odds ratio [OR], 3.61; 95% CI, 3.32-3.92), eating disorders (OR, 2.94; 95% CI, 1.96-4.41), and anxiety (OR, 2.61; 95% CI, 2.30-2.97). These associations were supported by consistent genetic correlations (rg) (depression rg, 0.36, P = 1.5 × 10 −9 ; anxiety rg, 0.33, P = 1.17 × 10 −5 ; and eating disorders rg, 0.61, P = .02). With the application of a 1-sample mendelian randomization, the genetic liabilities to depression and anxiety were associated with increased odds of endometriosis (depression: OR, 1.09; 95% CI, 1.08-1.11; anxiety: OR, 1.39; 95% CI, 1.13-1.65). A genome-wide analysis of pleiotropic associations shared between endometriosis and psychiatric disorders identified 1 locus, DGKB rs12666606, with evidence of pleiotropy between endometriosis and depression after multiple testing correction ( z = −9.46 for endometriosis, z = 8.10 for depression, P = 5.56 × 10 −8 ; false discovery rate q = 4.95 × 10 −4 ). Conclusions and Relevance These findings highlight that endometriosis is associated with women’s mental health through pleiotropic mechanisms. To our knowledge, this is the first large-scale study to provide genetic and phenotypic evidence of the processes underlying the psychiatric comorbidities of endometriosis.
An Implantable Bioprosthetic Venous Valve to Establish Deep Vein Competence for Post-Thrombotic Syndrome
Authors: Sebastian Cifuentes, Jorge H. Ulloa, Todd E. Rasmussen
Journal: JAMA Surgery (2023)

This article discusses the VenoValve bioprosthetic device, which is designed to improve valvular competence in the deep venous system of the lower extremities and treat deep venous insufficiency.
Defining Posttraumatic Sepsis for Population-Level Research
Authors: Katherine Stern, Qian Qiu, Michael Weykamp, Grant O’Keefe, Scott C. Brakenridge
Journal: JAMA Network Open (2023)

Importance Multiple classification methods are used to identify sepsis from existing data. In the trauma population, it is unknown how administrative methods compare with clinical criteria for sepsis classification. Objectives To characterize the agreement between 3 approaches to sepsis classification among critically ill patients with trauma and compare the sepsis-associated risk of adverse outcomes when each method was used to define sepsis. Design, Setting, and Participants This retrospective cohort study used data collected between January 1, 2012, and December 31, 2020, from patients aged 16 years or older with traumatic injury, admitted to the intensive care unit of a single-institution level 1 trauma center and requiring invasive mechanical ventilation for at least 3 days. Statistical analysis was conducted from August 1, 2021, to March 31, 2022. Exposure Hospital-acquired sepsis, as classified by 3 methods: a novel automated clinical method based on data from the electronic health record, the National Trauma Data Bank (NTDB), and explicit and implicit medical billing codes. Main Outcomes and Measures The primary outcomes were chronic critical illness and in-hospital mortality. Secondary outcomes included number of days in an intensive care unit, number of days receiving mechanical ventilation, discharge to a skilled nursing or long-term care facility, and discharge to home without assistance. Results Of 3194 patients meeting inclusion criteria, the median age was 49 years (IQR, 31-64 years), 2380 (74%) were male, and 2826 (88%) sustained severe blunt injury (median Injury Severity Score, 29 [IQR, 21-38]). Sepsis was identified in 747 patients (23%) meeting automated clinical criteria, 118 (4%) meeting NTDB criteria, and 529 (17%) using medical billing codes. The Light κ value for 3-way agreement was 0.16 (95% CI, 0.14-0.19). The adjusted relative risk of chronic critical illness was 9.9 (95% CI, 8.0-12.3) for sepsis identified by automated clinical criteria, 5.0 (95% CI, 3.4-7.3) for sepsis identified by the NTDB, and 4.5 (95% CI, 3.6-5.6) for sepsis identified using medical billing codes. The adjusted relative risk for in-hospital mortality was 1.3 (95% CI, 1.0-1.6) for sepsis identified by automated clinical criteria, 2.7 (95% CI, 1.7-4.3) for sepsis identified by the NTDB, and 1.0 (95% CI, 0.7-1.2) for sepsis identified using medical billing codes. Conclusions and Relevance In this cohort study of critically ill patients with trauma, administrative methods misclassified sepsis and underestimated the incidence and severity of sepsis compared with an automated clinical method using data from the electronic health record. This study suggests that an automated approach to sepsis classification consistent with Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) clinical criteria is feasible and may improve existing approaches to health services and population-based research in this population.
Rates of Follow-up Colonoscopy After a Positive Stool-Based Screening Test Result for Colorectal Cancer Among Health Care Organizations in the US, 2017-2020
Authors: Jeff T. Mohl, Elizabeth L. Ciemins, Lesley-Ann Miller-Wilson, Abbie Gillen, Roger Luo, Francis Colangelo
Journal: JAMA Network Open (2023)

Importance Noninvasive stool-based screening tests (SBTs) are effective alternatives to colonoscopy. However, a positive SBT result requires timely follow-up colonoscopy (FU-CY) to complete the colorectal cancer screening paradigm. Objectives To evaluate FU-CY rates after a positive SBT result and to assess the association of the early COVID-19 pandemic with FU-CY rates. Design, Setting, and Participants This mixed-methods cohort study included retrospective analysis of deidentified administrative claims and electronic health records data between June 1, 2015, and June 30, 2021, from the Optum Labs Data Warehouse and qualitative, semistructured interviews with clinicians from 5 health care organizations (HCOs). The study population included data from average-risk primary care patients aged 50 to 75 years with a positive SBT result between January 1, 2017, and June 30, 2020, at 39 HCOs. Main Outcomes and Measures The primary outcome was the FU-CY rate within 1 year of a positive SBT result according to patient age, sex, race, ethnicity, insurance type, Charlson Comorbidity Index (CCI), and prior SBT use. Results This cohort study included 32 769 individuals (16 929 [51.7%] female; mean [SD] age, 63.1 [7.1] years; 2092 [6.4%] of Black and 28 832 [88.0%] of White race; and 825 [2.5%] of Hispanic ethnicity). The FU-CY rates were 43.3% within 90 days of the positive SBT result, 51.4% within 180 days, and 56.1% within 360 days (n = 32 769). In interviews, clinicians were uniformly surprised by the low FU-CY rates. Rates varied by race, ethnicity, insurance type, presence of comorbidities, and SBT used. In the Cox proportional hazards regression model, the strongest positive association was with multitarget stool DNA use (hazard ratio, 1.63 [95% CI, 1.57-1.68] relative to fecal immunochemical tests; P &amp;amp;lt; .001), and the strongest negative association was with the presence of comorbidities (hazard ratio, 0.64 [95% CI, 0.59-0.71] for a CCI of &amp;amp;gt;4 relative to 0; P &amp;amp;lt; .001). The early COVID-19 pandemic was associated with lower FU-CY rates. Conclusions and Relevance This study found that FU-CY rates after a positive SBT result for colorectal cancer screening were low among an average-risk population, with the median HCO achieving a 53.4% FU-CY rate within 1 year. Socioeconomic factors and the COVID-19 pandemic were associated with lower FU-CY rates, presenting opportunities for targeted intervention by clinicians and health care systems.
A Woman With Recurrent Torsade de Pointes
Authors: Cody McCoy, John M. Miller, Tanyanan Tanawuttiwat
Journal: JAMA Cardiology (2023)

A woman in her mid-40s presented to the emergency department after a fall with head trauma. During day 15 of admission, the patient had 3 episodes of torsade de pointes while taking 50 mg of oral metoprolol succinate daily. What would you do next?
Analysis by Gender and Race and Ethnicity of Reviewers and Awardees for Intramural Research Funding in the Veterans Health Administration
Authors: Taylor L. Boyer, Utibe R. Essien, Terrence M. A. Litam, Leslie R. M. Hausmann, Katie J. Suda
Journal: JAMA Network Open (2023)

Underrepresentation of women and racial and ethnic minority individuals among reviewers and funded investigators in health research has been widely reported. It is unknown whether such underrepresentation exists in the Veterans Health Administration (VHA).To describe gender and racial and ethnic makeup of VHA Health Services Research and Development (HSR&D) study sections and funding awardees and to explore the associations between gender and racial and ethnic makeup of study sections and awardees who were women and racial and ethnic minority individuals.This cross-sectional study at the VHA evaluated study section members and funding awardees from 5 review cycles from March 13, 2018, through March 6, 2020, identified via the HSR&D and National Institutes of Health websites.Univariable and multivariable logistic regression models were used to determine the likelihood of an awardee being a woman or a racial or ethnic minority individual based on the gender and racial and ethnic makeup of study sections, respectively. Separate models were conducted for investigator-initiated research proposals only.Thirty-six study sections comprised 664 reviewers, including 381 women (57.4%) and 81 racial and ethnic minority individuals (12.2%). Of the 146 funded proposals, 77 (52.7%) were awarded to women and 25 (17.1%) to racial and ethnic minority investigators; 29 (19.9%) were reviewed by study sections with no racial and ethnic minority reviewers. The odds of a woman awardee were more than 5 times greater for proposals reviewed by study sections comprising the highest proportion of women (fourth quartile; >58.3%) than the lowest proportion of women (first quartile; ≤50.0%) (adjusted odds ratio [aOR], 5.24 [95% CI, 1.70-16.13]). Similarly, the odds of a racial or ethnic minority awardee were 3 times greater for proposals reviewed by study sections in the top 50th percentile for proportion of racial and ethnic minority individuals (>7.3%) than the bottom 50th percentile (aOR, 3.08 [95% CI, 1.18-8.09]). Secondary analyses limited to investigator-initiated research proposals identified similar associations.In this cross-sectional study of VHA HSR&D-funded research, racial and ethnic minority individuals were underrepresented among investigators and reviewers. More women and racial and ethnic minority reviewers on study sections were associated with women and racial and ethnic minority individuals awarded funding.
Etomidate vs Propofol in Older Surgical Patients—Reply
Authors: Zhihong Lu, Hailong Dong, Lize Xiong
Journal: JAMA Surgery (2023)

In Reply We appreciate the comments from Jing and Tian as well as Zhang regarding our clinical trial on postoperative in-hospital morbidity after etomidate general anesthesia compared with propofol general anesthesia.1 The authors raise some valuable points of discussion regarding our work.
Variability in Out-of-Pocket Costs and Quality for Common Emergency General Surgery Conditions
Authors: Pooja U. Neiman, Vibav H. Mouli, Kathryn K. Taylor, Zhaohui Fan, John W. Scott
Journal: JAMA Surgery (2023)

This cross-sectional study uses payment information from a larger commercial payer in the US to assess the out-of-pocket and total costs for emergency surgery from 2016 to 2019 in the context of quality of care.
Effects of Mavacamten on Measures of Cardiopulmonary Exercise Testing Beyond Peak Oxygen Consumption
Authors: Matthew T. Wheeler, Iacopo Olivotto, Perry M. Elliott, Sara Saberi, Anjali T. Owens, Mathew S. Maurer, Ahmad Masri, Amy J. Sehnert, Jay M. Edelberg, Yu-Mao Chen, Victoria Florea, Rajeev Malhotra, Andrew Wang, Artur Oręziak, Jonathan Myers
Journal: JAMA Cardiology (2023)

Mavacamten, a cardiac myosin inhibitor, improved peak oxygen uptake (pVO2) in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) in the EXPLORER-HCM study. However, the full extent of mavacamten's effects on exercise performance remains unclear.To investigate the effect of mavacamten on exercise physiology using cardiopulmonary exercise testing (CPET).Exploratory analyses of the data from the EXPLORER-HCM study, a randomized, double-blind, placebo-controlled, phase 3 trial that was conducted in 68 cardiovascular centers in 13 countries. In total, 251 patients with symptomatic obstructive HCM were enrolled.Patients were randomly assigned in a 1:1 ratio to mavacamten or placebo.The following prespecified exploratory cardiovascular and performance parameters were assessed with a standardized treadmill or bicycle ergometer test protocol at baseline and week 30: carbon dioxide output (VCO2), minute ventilation (VE), peak VE/VCO2 ratio, ventilatory efficiency (VE/VCO2 slope), peak respiratory exchange ratio (RER), peak circulatory power, ventilatory power, ventilatory threshold, peak metabolic equivalents (METs), peak exercise time, partial pressure of end-tidal carbon dioxide (PETCO2), and VO2/workload slope.Two hundred fifty-one patients were enrolled. The mean (SD) age was 58.5 (11.9) years and 59% of patients were male. There were significant improvements with mavacamten vs placebo in the following peak-exercise CPET parameters: peak VE/VCO2 ratio (least squares [LS] mean difference, -2.2; 95% CI, -3.05 to -1.26; P < .001), peak METs (LS mean difference, 0.4; 95% CI, 0.17-0.60; P < .001), peak circulatory power (LS mean difference, 372.9 mL/kg/min × mm Hg; 95% CI, 153.12-592.61; P = .001), and peak PETCO2 (LS mean difference, 2.0 mm Hg; 95% CI, 1.12-2.79; P < .001). Mavacamten also improved peak exercise time compared with placebo (LS mean difference, 0.7 minutes; 95% CI, 0.13-1.24; P = .02). There was a significant improvement in nonpeak-exercise CPET parameters, such as VE/VCO2 slope (LS mean difference, -2.6; 95% CI, -3.58 to -1.52; P < .001) and ventilatory power (LS mean difference, 0.6 mm Hg; 95% CI, 0.29-0.90; P < .001) favoring mavacamten vs placebo.Mavacamten improved a range of CPET parameters beyond pVO2, indicating consistent and broad benefits on maximal exercise capacity. Although improvements in peak-exercise CPET parameters are clinically meaningful, the favorable effects of mavacamten on submaximal exertional tolerance provide further insights into the beneficial impact of mavacamten in patients with obstructive HCM.ClinicalTrials.gov Identifier: NCT03470545.